Asthma, bronchitis and emphysema are known as Chronic Obstructive Pulmonary Diseases (COPD). COPD is characterized as generalized airways obstruction, particularly of small airways, associated with varying degrees of symptoms of chronic bronchitis, asthma, and emphysema. The term COPD was introduced because these conditions often coexist, and it may be difficult in an individual case to decide which is the major condition producing the obstruction. Airways obstruction is defined as an increased resistance to airflow during forced expiration. It may result from narrowing or obliteration of airways secondary to intrinsic airways disease, from excessive collapse of airways during a forced expiration secondary to pulmonary emphysema, from bronchospasm as in asthma, or may be due to a combination of these factors. Although obstruction of large airways may occur in all these disorders, particularly in asthma, patients with severe COPD characteristically have major abnormalities in their small airways, namely those less than 2 mm internal diameter, and much of their airways obstruction is situated in this zone. The airways obstruction is irreversible except for that which can be ascribed to asthma.
Asthma is a reversible obstructive pulmonary disorder (ROPD) characterized by increased responsiveness of the airways. Asthma can occur secondarily to a variety of stimuli. The underlying mechanisms are unknown, but inherited or acquired imbalance of adrenergic and cholinergic control of airways diameter has been implicated. Persons manifesting such imbalance have hyperactive bronchi and, even without symptoms, bronchoconstriction may be present. Overt asthma attacks may occur when such persons-are subjected to various stresses. Persons whose asthma is precipitated by allergens (most commonly airborne pollens and molds, house dust, animal danders) and whose symptoms are IgE-mediated are said to have allergic or "extrinsic" asthma. They account for about 10 to 20% of adult asthmatics; in another 30 to 50%, symptomatic episodes seem to be triggered by non-allergenic factors (e.g., infection, irritants, emotional factors), and these patients are said to have nonallergic or "intrinsic" asthma.
Formoterol (1), whose chemical name is (+/-) N-[2-hydroxy-5-[1-hydroxy-2[[2-(p-methoxyphenyl)-2-propyl]amino]ethyl]phen yl]-formamide is a highly potent and .beta..sub.2 -selective adrenoceptor agonist having a long lasting bronchodilating effect when inhaled. The structure of formoterol is as shown: ##STR1##
Formoterol's primary use is as a long-acting bronchodilator for the relief of reversible bronchospasm in patients with obstructive airway disease such as asthma, bronchitis and emphysema.
The class of .beta..sub.2 agonists, of which formoterol is a member, cause somewhat similar adverse effects. These adverse effects include but are not limited to central nervous system symptoms, such as hand tremors, muscle tremors, nervousness, dizziness, headache and drowsiness; respiratory side effects, such as dyspnea, wheezing, drying or irritation of the oropharynx, coughing, chest pain and chest discomfort; and cardiovascular effects, such as palpitations, increased heart rate, and tachycardia. According to Trofast et al. (op. cit.) (R,R) formoterol is primarily a chronotropic agent in vitro with inotropic effects showing up at higher concentrations. The chronotropic effects are reported at concentrations that are higher than those at which relaxation of tracheal muscle (bronchodilation) is seen. .beta.-Agonists (e.g. dobutamine) are known in general to exhibit inotropic activity. In addition, racemic .beta..sub.2 -agonists can cause angina, vertigo, central stimulation and insomnia, airway hyperreactivity (hypersensitivity), nausea, diarrhea, dry mouth and vomiting. As with other pharmaceuticals .beta..sub.2 -agonists sometimes cause systemic adverse effects such as weakness, fatigue, flushed feeling, sweating, unusual taste, hoarseness, muscle cramps and backaches.
Furthermore, patients may develop a tolerance to the bronchodilating effect of the racemic mixture of formoterol. This is related to desensitization, which is one of the most clinically significant phenomena involving the beta-adrenergic receptor. The problem of desensitization is especially significant in the treatment of diseases involving bronchospasms, such as asthma. The treatment of asthma usually involves the self-administration, either orally or by aerosol, of beta-adrenergic agonists such as the racemic (R,R) (S,S) mixture of formoterol. These agonists mediate bronchodilation and promote easier breathing. Asthmatic patients utilizing .beta.-agonists for a prolonged time gradually increase the self-administered dose in order to get a sufficient amount of bronchodilation and relief in breathing. As a result of this increased dosage, the agonist concentration builds to a sufficient level so as to enter the peripheral circulation where it acts on the beta receptors of the heart and vasculature to cause cardiovascular stress and other adverse effects.
Formoterol has two chiral centers (denoted by the asterisks in formula 1), each of which can exist in two possible configurations. This gives rise to four combinations: (R,R), (S,S), (R,S) and (S,R). (R,R) and (S,S) are mirror images of each other and are therefore enantiomers; (R,S) and (S,R) are similarly an enantiomeric pair. The mirror images of (R,R) and (S,S) are not, however, superimposable on (R,S) and (S,R), which are diastereomers. Formoterol is available commercially only as a mixture of (R,R) plus (S,S) in a 1:1 ratio, and the generic name formoterol refers to this racemic mixture. The racemic mixture that is commercially available for administration is a dihydrate of the fumarate salt of the formula shown: ##STR2##
The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr J. Chem. Ed. 62, 114-120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. Thus, the formula for formoterol above reflects the racemic nature of the commercial material, while among the structures below, those having open wedges are intended to encompass a pure, single configuration which is one of the two possible at that carbon, and those having solid wedges are intended to encompass the single, pure isomer having the absolute stereochemistry shown.
3-Amino-4-hydroxy-.alpha.-[[[2-(4-methoxyphenyl)- 1-methylethyl]amino]methyl]-benzenemethanol (Chem. Abst. Reg. No. 150513-24-9). which is referred to hereinafter as "desformoterol" (2), has been disclosed as an undesired side product in a synthesis of formoterol (Spanish Patent ES 2031407). Its structure is shown below. ##STR3##
Neither its deliberate synthesis nor its pharmacology has been previously reported. It too exists in four isomeric forms.
All four isomers of formoterol have been synthesized and briefly examined for relaxing activity on the guinea pig trachea [Murase et al., Chem. Pharm. Bull. 26, 1123-1129 (1978). It was found that the (R,R)-isomer is the most potent, while the others are 3-14 times less potent. More recently, the four isomers have been examined with respect to their ability to interact in vitro with .beta.-adrenoceptors in tissues isolated from guinea pig [Trofast et al., Chirality 3, 443-450 (1991)]. The order of potency was (R,R)&gt;&gt;(R,S)=(S,R)&gt;(S,S). It was found that the (R,R)-isomer is 1000-fold more potent than the (S,S)-isomer. Trofast concluded that "Since the (S,S)-enantiomer is practically inactive there is from this point of view no reason for its removal from the racemate in pharmaceutical preparations . . . " In contradistinction, U.S. Pat. No. 5,795,564 indicates that administration of the pure (R,R)-isomer provides significant therapeutic advantages, particularly in avoiding or ameliorating the side effects seen with racemic formoterol (i.e. 1:1 RR/SS isomers). No art appears to suggest any advantage to the use of the pure S,R isomer. In fact, it is one of the two isomers that has for twenty years been removed from the commercial formoterol product.
Thus the general conclusion among persons of skill in the art is that, if there is any advantage to an individual isomer, it resides in the R,R isomer. However, we have discovered that there are practical problems associated with the preparation of pharmaceutical dosage forms of racemic and R,R formoterol. These problems arise from the extraordinary potency of racemic and R,R formoterol; it is simply too potent to conveniently formulate for a metered dose inhaler. Since it is active on. the microgram level, if even a small amount of active ingredient sticks to the inhaler, e.g. to the valve components or other interior portions of the canister, significant overdosing can arise when it is released on a subsequent activation. There is therefore a need for a medicament having the advantages of R,R formoterol but less potential for dose-to-dose variability in formulations.